Pancreatic cancer is one of the major unsolved problems in general surgery today. Pancreatic cancer has a dismal 5 year of less than 5%, and while the safety of surgery has improved, surgical treatment has not had a significant imapct on survival. Only a better understanding of the basic biology of pancreatic tumorigenesis will allow effective treatment of this disease. TGFbeta is an important regulator of pancreatic growth and differentiation. Recently, deleted in pancreatic carcinoma 4 (DPC4) was identified as a tumor suppressor gene that is inactivated in 50% of pancreatic tumors. DPC4 (also known as Smad4) is a signaling molecule in TGFbeta -related signaling pathways. Many human pancreatic cancer cell lines are refractory to growth inhibitory effects of TGFbeta. While the TGFbeta signaling pathway has been studied in several cultured cell lines, TGFbeta affects a wide variety of cellular responses and significant differences exist in this in this complex signaling pathway in different cells. The intracellular signaling pathways through which TGFbeta acts to generate cellular responses in the pancreas remain largely undefined. The pancreas, with its high incidence of mutations in this pathway and the likely importance of Smads in pancreatic, is arguably one of the most important tissues in which to investigate this pathway. The current research proposal is designed to investigate, on a fundamental level, TGFbeta signaling and the role of Smads in pancreatic acinar cells. We have hypothesized that: 1) Smad genes are required for growth inhibition and regulation of differentiation by TGFbeta in pancreatic in acinar cells; 2) MAP kinases interact with TGFbeta/Smad signaling; 3) TGFbeta- mediated induction of transcription factors in pancreatic acinar cells is regulated by both the Smad and MAP kinase signaling pathways; and 4) functional inactivation of Smad4 results in abnormal proliferation and dedifferentiation in the pancreas in vivo. These studies will help to elucidate the molecular events by which TGFbeta regulates growth and differentiation in normal pancreatic tissues and will likely reveal crucial insight into the mechanisms important in neoplatstic in the pancreas. This grant proposal is submitted for the Small Grants Program for K08 Recipients-NIH K08 DK02637-01.